Summary of Work: Airway epithelial cells express receptors for pro- inflammatory cytokines, such as tumor necrosis factor (TNF-alpha) and interleukin-1 (IL-1), and therefore represent target cells for autocrine- or paracrine-acting cytokines. Airway epithelial cells may modulate cytokine-mediated events via the shedding of cell surface receptors or by the production of receptor antagonists. Airway epithelial cells express the 55 kDa type I TNF receptor, which can be proteolytically cleaved to function as a soluble TNF binding protein. We have reported that protein kinase C activation by phorbol esters or IL-1beta can induce shedding of the 55 kDa type I TNF receptor from human airway epithelial cells (HAECs), which is associated with a decrease in total cellular 55 kDa type I TNF receptor numbers. Conversely, corticosteroids inhibit TNF receptor shedding and increase total cellular 55 kDa type I TNF receptor numbers. Studies are now underway to investigate the mechanisms underlying TNF receptor shedding and to identify the enzyme responsible for proteolytic cleavage. HAEC also express the type l intracellular isoform of the IL-I receptor antagonist (iclL-lRa type I). We have reported that corticosteroids induce icILIRa type I mRNA and protein as a mechanism by which IL-1 mediated airway inflammatory events might be attenuated. Another manuscript has been completed describing the differential regulation of icIL-IRa type I release from HAECs by corticosteroids and cytokines. lL- 4, IL-I 3, and interferon-gamma induce icIL-IRa type I release to the extracellular compartment while corticosteroids inhibit release, thereby allowing for the accumulation of icIL-1Ra type I within the intracellular compartment. Additional studies are in progress to investigate the mechanism underlying icIL-1Ra type I release and to understand its role as a regulator of intracellular IL-1 bioactivity. An increased understanding of the mechanisms by which epithelial cells modulate responses to inflammatory cytokines may allow for the development of new therapeutic approaches to reduce airway inflammation.